Research on epilepsy: Damage control

As a physician-scientist specializing in epilepsy, Jeffrey Noebels, MD,
PhD, sees the profound effect the disease has on his patients daily
lives, from preventing them from holding down jobs to simply driving down
the block.

He does his best to help them manage their disease by prescribing medications
to reduce the severity and frequency of their seizures. Surgery is another
option for patients who don't respond to medication and is usually
an effective one, eliminating an estimated 80 percent of seizures.

But while current treatments for epilepsy reduce the number of seizures
in epilepsy patients, they don't affect the amount of damage inflicted
by seizures on the brain. Noebels lab is investigating why the
severity of seizure damage varies from person to person--causing severe
damage to one while leaving another relatively unscathed.

One of the newest concepts in epilepsy is that specific genes
may determine whether a person will have a seizure or not, while others
may control the amount of damage caused by the seizure, Noebels
said.

Noebels, recently elected president of the American Epilepsy Society,
is a professor in the departments of neurology and molecular and human
genetics and director of the Blue Bird Circle Developmental Neurogenetics
Laboratory at Baylor College of Medicine. Funded by a continuing grant
from the National Institutes of Health, he and his colleagues have been
searching for genes that might be linked to epilepsy since the labs
start in 1986. Now, he believes they have found a gene that may help protect
the brain from cell death caused by seizures.

In people with severe epilepsy, cell death is a major cause of
cognitive problems and memory loss, Noebels said.

We compared two strains of mice, one that was seizure-damage resistant
to another strain that was vulnerable to seizure damage, he continued.
We were able to isolate several genes expressed that have long
been known as neuroprotective, but one had never been seen in the brain
before.

After isolating the gene, a member of the bcl2 gene family, Mayra Mori,
PhD, a postdoctoral fellow in Noebels laboratory, found that in
the presence of this gene, brain cells were much less likely to die. To
test his theory further, they obtained from Harvard University a knockout
mouse lacking the gene. Then they induced seizures in the mice and analyzed
the brain tissue. The knockout mice had severe brain damage.

The results showed that the gene was able to protect against seizure-induced
cell death, and thus contributed to the difference between these strains
of mice, Noebels said.

But do humans have this gene? Using post-mortem brain tissue samples,
the laboratory found the gene in patients whose brains had suffered severe
damage. Testing brain biopsies from epilepsy patients undergoing surgery
might be the next step, Noebels said.

It has been a challenge to find which genes might make the difference
between a patient whose brain is protected from the cell death and whose
brain is not, Noebels said. Once you have that molecule,
you have an additional target, a validated target, to discover a drug
to modify the amount of that gene in your brain, and then to determine
whether that could work in emergency situations.

Finding neuroprotective genes could also be important in treating other
conditions that involve cell death, such as stroke or concussions.

There might be a window of opportunity to prevent cells from dying
for couple of days after the seizure or stoke, Noebels said. It
is always important to find new targets, and every new molecule we investigate
offers another opportunity.